Adenovirus mediated expression of human paraoxonase 2 protects against the development of atherosclerosis in apolipoprotein E-deficient mice

Accumulating evidence suggests that the oxidative modification of low-density lipoprotein (LDL) plays an integral role in the initiation and progression of atherosclerosis. We have previously reported that human paraoxonase (PON) 2 possesses antioxidant properties and is capable of preventing LDL oxidation in vitro. The objective of this study was to determine whether elevated levels of PON2 could protect against the development of atherosclerosis in vivo. Six-month-old apolipoprotein E-deficient mice (apoE−/−) were injected intravenously with either PBS or 3 × 1011 particles of adenovirus expressing GFP (AdGFP) or human PON2 (AdPON2). Three weeks post-injection, lesion area was significantly lower in mice treated with AdPON2 compared to their control counterparts. Serum from AdPON2 treated mice contained significantly lower levels of lipid hydroperoxides and exhibited an enhanced potential to efflux cholesterol from cholesterol-loaded macrophages. In addition, LDL from AdPON2 treated mice was less susceptible to oxidation, while HDL from these same mice was significantly more capable of protecting LDL against oxidation. These results demonstrate for the first time that elevated levels of PON2 can enhance the efflux potential and antioxidant capacity of serum, increase the anti-inflammatory properties of HDL, and protect against the development of atherosclerosis in vivo.